Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find the mechanism by which cells resist chemotherapy

05.03.2007
A team of researchers from the UAB's Mutagenesis Group, led by Doctor Jordi Surralés, has identified one of the mechanisms used by cancer cells to resist chemotherapy. This discovery, published in The EMBO Jorunal, will make it possible to develop strategies to make tumours more vulnerable to chemotherapy.

In his paper, published in The EMBO Jorunal, Dr Surrallés describes how proteins of the Fanconi/BRCA pathway recognise the presence of genetic mutations in order to repair them. The researchers also found that alteration of this mechanism makes tumour cells much more sensitive to certain drugs. This discovery will make it possible to develop strategies to make tumours more vulnerable to chemotherapy.

One of the main mechanisms responsible for repairing mutations in humans is the cancer-suppressing Fanconi anaemia/BRCA pathway. This mechanism makes it possible for the cells to identify genetic mutations in order to correct them.

If this mechanism does not function correctly, it leads to Fanconi anaemia, a rare genetic disorder characterised by progressive bone-marrow failure, various congenital malformations and a very high risk of cancer.

Furthermore, the proteins of this pathway are largely responsible for the resistance of tumours to many antitumour agents such as cisplatin and other chemotherapeutic agents that kill tumour cells by producing DNA interstrand crosslinks. That is, they identify cellular alterations induced by chemotherapy and correct them, "accidentally" helping the tumour.

Many tumours have molecular anomalies in this pathway. These defects mean the tumours can be treated efficiently using certain antitumour agents. There are at least 13 genes involved in the pathway. Three of these (BRCA2, BRIP1 and PALB2) are responsible for the high proportion of hereditary breast cancers (between 5 and 10% of all breast cancers).

Understanding how this DNA repair pathway works is of great interest to biomedicine, not only for Fanconi anaemia patients, but also for the general cancer population, since it determines the the efficacy of chemotherapy in treating many tumours. However, the involvement of 13 genes in the same pathway makes the study more complexed.

A team of researchers from the UAB's Mutagenesis Group, led by Doctor Jordi Surralés, has identified one of the important unresolved questions regarding this pathway: how the Fanconi anaemia proteins detect the presence of mutations so they can repair them.

The researchers have found that the mutations block the DNA replication process, a process that is necessary, especially in tumour tissues, for the cells to be able to divide and proliferate. By blocking the replication process, the mutations activate a type of enzyme, the ATR kinase, which phosphorylates (introduces phosphate groups into) histone H2AX, a protein present in the chromatin that surrounds the damaged DNA. The phosphorylated histone H2AX indicates the location of the genetic damage to the Fanconi proteins and places them in exactly the right place to repair the DNA.

The researchers have shown that one of the 13 Fanconi proteins, the FANCD2, binds directly to the phosphorylated histone H2AX. The BRCA1 protein also plays a part in this process and, alongside the BRCA2, it is involved in most hereditary breast cancers. So these proteins cooperate in repairing the genetic damage, preserving the stability of the chromosomes and preventing the onset of tumours.

This research will have many implications on biomedicine. The increase in knowledge on this pathway will make it possible to design strategies for the chemosensitisation of tumour cells. Dr Jordi Surallés's team has also observed that many breast cancer cell lines are between two to three times more sensitive to chemotherapy if they have partially inhibited the Fanconi FANCD2 gene expression.

The results of this study, carried out entirely within the UAB Department Of Genetics and Microbiology, will be published in The EMBO Journal. Most of the work was carried out by the post-doctoral researchers Massimo Bogliolo and Alex Lyakhovich. The group directed by Dr Jordi Surallés is funded by the EU commission, the FEDER fund, the Spanish Ministry of Education and Science, the Spanish Ministry of Health and Consumption, Fundación La Caixa, Genoma España and the Centro de Investigación Biomédica en Red en Enfermedades Raras.

Octavi López Coronado | alfa
Further information:
http://www.uab.es

Further reports about: DNA Jordi chemotherapy genetic mutation mechanism tumour

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>